Mechanism of inhibition of acid-mediated transthyretin aggregation by designed peptides.

ABSTRACT: Aggregation of transthyretin (TTR) causes TTR cardiomyopathy and polyneuropathy through amyloidosis. To initialize TTR aggregation, the native TTR tetramer first dissociates to a monomeric intermediate, which misfolds and self-assembles to oligomers, eventually forming insoluble aggregates and fibrils. Peptide inhibitors have been designed to cap two β-strands that are buried in the well-folded tetramer but are solvent-exposed in the monomeric aggregation intermediate. However, how these peptides affect the reaction kinetics of individual steps in the multi-step TTR aggregation pathway remains unknown. Here, we integrated ¹⁹F-NMR and kinetic modeling to determine aggregation reaction rates of individual steps with the peptide inhibitors and extract the free energy landscape alon

SUBMITTER: Sun X 

PROVIDER: S-EPMC12624794 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature